Abstract:

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. FD
causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including
the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction,
which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis,
angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge
about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously
progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms
and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than
males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the
disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation
of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis
of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of
glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect
early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral
disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific
vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction,
alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations
(Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function,
mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The
neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide
accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS
is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid
appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive
abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional
control of the vessels, secondary to endothelial dysfunction as a consequence of -galactosidase A deficiency. The diagnosis of Fabry
disease is made in hemizygous males after the detection of the presence of angiokeratomas (Fig. 19 A, B), irregularities in sweating,
edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement.
A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis
in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels
within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development
of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index
(MSSI) (Table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry
disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients
with AFD was significantly higher than that of patients with other severe debilitating diseases.

Abstract:Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. FD
causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including
the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction,
which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis,
angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge
about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously
progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms
and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than
males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the
disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation
of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis
of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of
glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect
early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral
disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific
vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction,
alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations
(Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function,
mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The
neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide
accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS
is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid
appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive
abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional
control of the vessels, secondary to endothelial dysfunction as a consequence of -galactosidase A deficiency. The diagnosis of Fabry
disease is made in hemizygous males after the detection of the presence of angiokeratomas (Fig. 19 A, B), irregularities in sweating,
edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement.
A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis
in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels
within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development
of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index
(MSSI) (Table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry
disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients
with AFD was significantly higher than that of patients with other severe debilitating diseases.